The present invention relates generally to processes for the preparation of 1,3,5-trisubstituted pyrazoles and intermediates for the synthesis of the same, such pyrazoles being useful as factor Xa inhibitors.
1,3,5-Trisubstituted-pyrazole compounds of the type shown below are currently being studied as factor Xa inhibitors in clinical settings. As one of ordinary skill in the art understands, clinical trials and NDA submissions require practical, large-scale synthesis of the active drug. 
Consequently, it is desirable to find new synthetic procedures for making 1,3,5-trisubstituted pyrazoles.
Accordingly, one object of the present invention is to provide a novel process for making 1,3,5-trisubstituted pyrazoles.
It is another object of the present invention to provide novel intermediates for the syntheses of the same 1,3,5-trisubstituted pyrazoles.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula I can be formed from aryl hydrazines. 
Thus, in a first embodiment, the present invention provides a novel process for preparing a compound of formula I: 
wherein ring D is selected from 2-(aminomethyl)phenyl, 3-(aminomethyl)phenyl, and (3-amino)benz[d]isoxazol-6-yl; and
B is 2-MeSO2-phenyl or 2-NH2SO2-phenyl, the process comprising:
(a) acylating a hydrazine of formula II to form a compound of formula III: 
xe2x80x83wherein ring D is selected from 2-cyanophenyl, 3-cyanophenyl, 3-cyano-4-fluorophenyl, 2-(PgNHCH2)phenyl, and 3-(PgNHCH2)phenyl, and Pg is an amine protecting group;
(b) converting a compound of formula III to a compound of formula IV, wherein X is selected from Cl, OMs, Br, OSO2Ph, and OTs;
(c) contacting a compound of formula IV with a base to form a dipolar compound of formula V: 
(d) contacting a compound of formula V in situ with a dipolarophile of formula VI to form a compound of formula VII, wherein Y is selected from Br, 2-MeSO2-phenyl, 2-MeS-phenyl, 2-NH2SO2-phenyl, and 2-PgNHSO2-phenyl;
(e) converting a compound of formula VII to a compound of formula I by subjecting it to the following reactions, which may be performed, when applicable, in any order:
(e1) oxidizing the pyrazoline to a pyrazole;
(e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO2Me-phenyl, or 2-SO2NH2-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO2xe2x80x94;
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH2)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz [d]isoxazol-6-yl; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, step (b) is performed by contacting a compound of formula III with a sulfonyl chloride in the presence of an amine base, wherein the amine base is capable of forming a tertiary amine hydrogen chloride in situ and delivering a chloride in situ to form a compound of formula IV wherein X is Cl;
wherein the sulfonyl chloride is selected from methylsulfonyl chloride, phenylsulfonyl chloride and toluenesulfonyl chloride, the amine base is selected from triethylamine, diisopropylethylamine, and N-methylmorpholine.
In another embodiment, the sulfonyl chloride is phenylsulfonyl chloride and the amine base is diisopropylethylamine.
In another embodiment, step (b) is performed by contacting a compound of formula III with a sulfonyl chloride in the presence of an amine base, followed by contacting the resultant sulfonyl compound with a tertiary amine hydrogen chloride to form a compound of formula IV wherein X is Cl;
wherein the sulfonyl chloride is selected from methylsulfonyl chloride, phenylsulfonyl chloride and toluenesulfonyl chloride, the amine base is selected from triethylamine, diisopropylethylamine, and N-methylmorpholine.
In another embodiment, in (e) the compound of formula VII is converted to a compound of formula I by subjecting compound VII to the following reactions, that are performed, when applicable, in the order shown:
(e1) oxidizing the pyrazoline to a pyrazole;
(e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO2Me-phenyl, or 2-SO2NH2-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO2xe2x80x94;
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH2)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, in (e) the compound of formula VII is converted to a compound of formula I by subjecting compound VII to the following reactions, that are performed, when applicable, in the order shown:
(e1) oxidizing the pyrazoline to a pyrazole;
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH2)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl;
(e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO2Me-phenyl, or 2-SO2NH2-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO2xe2x80x94; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, in (e) the compound of formula VII is converted to a compound of formula I by subjecting compound VII to the following reactions, that are performed, when applicable, in the order shown:
(e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO2Me-phenyl, or 2-SO2NH2-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO2xe2x80x94;
(e1) oxidizing the pyrazoline to a pyrazole;
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH2)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, in (e) the compound of formula VII is converted to a compound of formula I by subjecting compound VII to the following reactions, that are performed, when applicable, in the order shown:
(e2a) when Y=Br, converting the Br group to 2-SO2Me-phenyl or 2-SO2NH2-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO2xe2x80x94;
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH2)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl;
(e1) oxidizing the pyrazoline to a pyrazole; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, in (e) the compound of formula VII is converted to a compound of formula I by subjecting compound VII to the following reactions, that are performed, when applicable, in the order shown:
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH2)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl;
(e1) oxidizing the pyrazoline to a pyrazole;
(e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO2Me-phenyl, or 2-SO2NH2-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO2xe2x80x94; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, in (e) the compound of formula VII is converted to a compound of formula I by subjecting compound VII to the following reactions, that are performed, when applicable, in the order shown:
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH2)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl;
(e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO2Me-phenyl, or 2-SO2NH2-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO2xe2x80x94;
(e1) oxidizing the pyrazoline to a pyrazole; and,
(e4) when Pg is present, removing the protecting group.
In a second embodiment, the present invention provides a novel process for preparing a compound of formula I: 
wherein ring D is 2-(aminomethyl)phenyl, 3-(aminomethyl)phenyl, or (3-amino)benz[d]isoxazol-6-yl and B is 2-MeSO2-phenyl or 2-NH2SO2-phenyl, the process comprising:
(f) acylating a hydrazine of formula II to form a compound of formula III: 
xe2x80x83wherein ring D is selected from 2-cyanophenyl, 3-cyanophenyl, 3-cyano-4-fluorophenyl, 2-(PgNHCH2)phenyl, and 3-(PgNHCH2)phenyl, and Pg is an amine protecting group;
(g) converting a compound of formula III to a compound of formula IV, wherein X is selected from Cl, OMs, Br, OSO2Ph, and OTs;
(h) contacting a compound of formula IV with a base to form a dipolar compound of formula V: 
(i) contacting a compound of formula V in situ with a dipolarophile of formula VIa to form a compound of formula VIIa, wherein R is selected from H, Me, Et, and n-Pr;
(j) converting a compound of formula VIIa to a compound of formula I by subjecting it to the following reactions, which may be performed, when applicable, in any order:
(e1) oxidizing the pyrazoline to a pyrazole;
(j1) when R is other than H, hydrolyzing the compound of formula VIIa to its corresponding acid;
(j2) when R is H, contacting the acid of formula VIIa with an aniline of formula Vib to form an amide; 
xe2x80x83wherein Y is selected from Br, 2-MeSO2-phenyl, 2-MeS-phenyl, 2-NH2SO2-phenyl, and 2-PgNHSO2-phenyl;
(e2axe2x80x2) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO2Me-phenyl, or 2-SO2NH2-phenyl;
(e2bxe2x80x2) when Y=2-MeS-phenyl, converting the MeS-group to MeSO2xe2x80x94;
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH2)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, the present invention provides novel compounds of formula IX: 
wherein ring D is 2-cyanophenyl, 2-(PgNHCH2)phenyl, 2-(aminomethyl)phenyl, 3-cyanophenyl, 3-(PgNHCH2)phenyl, 3-(aminomethyl)phenyl, 3-cyano-4-fluorophenyl, and (3-amino)benz[d]isoxazol-6-yl;
Yxe2x80x2 is selected from Br, H, PgHNSO2Ph, H2NSO2Ph, 2-MeSPh, and 2-MeSO2Ph;
bond a is absent or is a single bond; and,
Pg is an amine protecting group selected from Boc and TFA.
In another embodiment, the present invention provides novel compounds of formula X: 
wherein R is selected from H, Me, Et, and n-Pr;
ring D is 2-cyanophenyl, 2-(PgNHCH2)phenyl, 2-(aminomethyl)phenyl, 3-cyanophenyl, 3-(PgNHCH2)phenyl, 3-(aminomethyl)phenyl, 3-cyano-4-fluorophenyl, and (3-amino)benz[d]isoxazol-6-yl;
bond a is absent or is a single bond; and,
Pg is an amine protecting group selected from Boc and TFA.
The present invention can be practiced on multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferable in the sale wherein at least one starting material is present in 10 grams or more, more preferable at least 05 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilo of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory sale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
As used herein, equivalents are intended to mean molar equivalents unless otherwise specified.
As used herein, the term xe2x80x9camino protecting groupxe2x80x9d (or xe2x80x9cN-protectedxe2x80x9d) refers to any group known in the art of organic synthesis for the protection of amine groups. As used herein, the term xe2x80x9camino protecting group reagentxe2x80x9d refers to any reagent known in the art of organic synthesis for the protection of amine groups that may be reacted with an amine to provide an amine protected with an amine-protecting group. Such amine protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991) and xe2x80x9cThe Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York, (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl (TFA), phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (cbz) and substituted benzyloxycarbonyls, 2-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.
Amine protecting groups may include, but are not limited to the following: 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl)]methyloxycarbonyl; 2-trimethylsilylethyloxycarbonyl; 2-phenylethyloxycarbonyl; 1,1-dimethyl-2,2-dibromoethyloxycarbonyl; 1-methyl-1-(4-biphenylyl)ethyloxycarbonyl; benzyloxycarbonyl; p-nitrobenzyloxycarbonyl; 2-(p-toluenesulfonyl)ethyloxycarbonyl; m-chloro-p-acyloxybenzyloxycarbonyl; 5-benzyisoxazolylmethyloxycrbonyl; p-(dihydroxyboryl)benzyloxycarbonyl; m-nitrophenyloxycarbonyl; o-nitrobenzyloxycarbonyl; 3,5-dimethoxybenzyloxycrbonyl; 3,4-dimethoxy-6-nitrobenzyloxycarbonyl; Nxe2x80x2-p-toluenesulfonylaminocarbonyl; t-amyloxycarbonyl; p-decyloxybenzyloxycarbonyl; diisopropylmethyloxycarbonyl; 2,2-dimethoxycarbonylvinyloxycarbonyl; di(2-pyridyl)methyloxycarbonyl; 2-furanylmethyloxycarbonyl; phthalimide; dithiasuccinimide; 2,5-dimethylpyrrole; benzyl; 5-dibenzylsuberyl; triphenylmethyl; benzylidene; diphenylmethylene; and, methanesulfonamide.
By way of example and without limitation, the present invention may be further understood by the following schemes and descriptions.

This reaction involves the acetylating of an arylhydrazine (II) or a salt thereof (e.g., HCl) with an acetylating reagent (e.g., trifluoroacetic anhydride (TFAA)) to produce the corresponding aceytlated arylhydrazine (III). From about 1.0-1.1 equivalents of acetylating reagent are used, preferably about 1.0 equivalent, especially when the reaction is run on large scale. Surprisingly, no base is necessary to run the acetylation. A base may be used, if desired. The preferred reaction temperature is about 0-25xc2x0 C. In order to control the internal temperature and maintain it at or below 25xc2x0 C., the acetylating reagent addition rate is adjusted accordingly. Such temperature control avoids formation of the bis-trifluoroacetylated by-product. The reaction is normally complete in about 1-2 h at from 0-25xc2x0 C. Preferably, THF is used as solvent, though other aprotic solvents can be used. The product is isolated by stripping off most of the solvent (i.e., THF) in vacuo when the reaction is complete and titrating the residue with a non-polar solvent, such as a hydrocarbon (e.g., heptanes) to precipitate the product, that is pure enough to carry forward without further purification.

The 1,3-dipole used in the present invention is a nitrileimine (V), which is generated by treating its precursor (IV), such as hydrazonoyl halide (IVa or IVb) or a hydrazonoyl sulfate (IVC, IVd, or IVe), with a base. The in situ generated nitrileimine (V) can be directly reacted with a dipolarophile, such as a substituted alkene, to produce the corresponding cycloaddition product, such as a substituted pyrazoline. The procedure for preparation of the corresponding hydrazonoyl bromide (IVa) and hydrazonoyl chloride (IVb) has been previously described (see Chem. Pharm. Bull. 1988, 36(2), 800).

About 1.0-1.5 equivalents of sulfonyl chloride is used, with the preferred molar ratio being about 1.05-1.1. Preferred sulfonyl chlorides are methyl sulfonyl chloride, phenyl sulfonyl chloride and toluenyl sulfonyl chlorde, with phenyl sulfonyl chloride being most preferred. A base is used to initiate the sulfonation reaction. The preferred base is a trialkylamine (pKa 10-11), such as triethylamine or diisopropylethylamine (Hunig""s base), or a cyclic tertiary amine (pKa 7-8), such as N-methylmorpholine (NMM), with diisopropylethylamine being most preferred. When substrate (III) contains electron-withdrawing functional group(s) on its aromatic ring, a cyclic tertiary amine is the preferred base; on the other hand, when substrate (III) contains electron-donating functional group(s) on its aromatic ring, a trialkylamine is preferred. The preferred reaction temperature is from 0-25xc2x0 C. The reaction time depends on the reactivity of the substrate (III) and the sulfonating agent. Normally, the sulfonation reaction is complete in 1-4 h at 0-25xc2x0 C. The preferred solvents for this sulfonation reaction are ethyl acetate (EtOAc), toluene or methylene chloride, with EtOAc being most preferred.
The regioselectivity of the sulfonation reaction (oxygen vs nitrogen) depends mainly on the reactivity of substrate (III). Selective O-sulfonation can be reached (oxygen vs nitrogen greater than 20:1) when an electron-deficient arylhydrazine (III) (e.g., trifluoroacylated arylhydrazine) is used. However, the regioselectivity is reduced dramatically (oxygen vs nitrogen less than 4:1) when an electron-enriched trifluoroacylated arylhydrazine (III) is employed. Therefore, the nucleophilicity and basicity of the nitrogen atom connected to the aromatic ring is greatly affected by the ring substitution pattern. The choice of base can also affect this selectivity.
The present invention also provides a novel and efficient preparation of hydrazonoyl sulfonates (IVc, IVd, and IVe) as the corresponding 1,3-dipole precursors in the cycloaddition reaction. 
The hydrazonoyl sulfonates (IVc, IVd, or IVe) can be readily transformed in situ into the corresponding hydrazonoyl chloride (IVb) by reacting with an in situ generated tertiary amine hydrogen chloride salt. Phenyl sulfonyl chloride is the preferred sulfonating reagent for this in situ reaction. For large-scale synthesis, this protocol for the preparation of hydrazonoyl chloride (IVb) can be very convenient. Compared with the literature-reported protocol (see Chem. Pharm. Bull. 1988, 36(2), 800), this methodology eliminates the use of the toxic carbon tetrahalide and large amounts of triphenylphosphine.
Hydrazonoyl sulfonates (IVc, IVd, and IVe) can be quantitatively converted into the corresponding hydrazonoyl chloride (IVb) by reacting with in situ generated trialkylamine hydrogen chloride salt or cyclic tertiary amine hydrogen chloride salt. This is a particularly useful reaction for the preparation of the hydrazonoyl chloride (IVb). Hydrazonoyl chloride (IVb) formation through this in situ transformation from the corresponding hydrazonoyl sulfonates (IVc-e) is affected by the reactivity of the particular tertiary amine hydrogen chloride salt. Compared with the cyclic tertiary amine hydrogen chloride salt, the trialkylamine hydrogen chloride salt is a better chlorinating agent to affect this transformation. Consequently, diisopropylethylamine is a most preferred base for this in situ reaction. In general, hydrazonyl sulfates (IVc, IVd, and IVe) are the kinectically favored products and can be obtained by quenching the sulfonation reaction with water at lower temperatures in short reaction periods. However, the thermodynamic product will be hydrazonoyl chloride (IVb) exclusively if the reaction is conducted at higher temperatures for relatively longer periods of time.

Preferably, about 1.0-1.1 equivalents of sulfonic anhydride agent are used. A weak base is used in the reaction to promote it. Pyridine (pKa 5.15) is a preferred base for this reaction, even though it is not strong enough to initiate the sulfonation reaction between sulfonyl chloride and trifluoroacylated arylhydrazine (III) in the alternative approach detailed above. The preferred reaction temperature is from 0-25xc2x0 C. The reaction is usually complete in 1-2 h at 0-25xc2x0 C. The preferred solvent is EtOAc.
Because the sulfonic anhydride is a relatively stronger sulfonating agent compared with the corresponding sulfonyl chloride used in approach A, the sulfonation reaction between the substrate (III) carrying the electron-withdrawing functional group(s) on its aromatic ring and the sulfonic anhydride is more regioselective. However, for the substrate (TII) carrying the electron-donating functional group(s) on its aromatic ring, little improvement for the regioselectivity was observed in this alternative reaction.
This approach produces only the desired hydrazonoyl sulfonate (IVc-e), no corresponding hydrazonoyl chloride (IVb) is generated because of the absence of a chloride source, such as tertiary amine hydrogen chloride salt, in the reaction mixture. Therefore, it can be used as the method to prepare pure hydrazonoyl sulfonates (IVc-e).

Acrylamides (VIb and VIc) are formed by reacting acryloyl chloride and a substituted aniline. A base is used to promote the reaction. Preferably, 1.0-2.0 equivalents of acryloyl chloride are used, more preferably about 1.2-1.5 equivalents. A trialkylamine, such as triethylamine, or a cyclic tertiary amine, such as N-methylmorpholine (NMM) is used as a base to promote this reaction, with NMM being preferred. A preferred solvent is EtOAc, THF, CH2Cl2, or acetonitrile, with EtOAc being more preferred. The reaction is preferably run at a temperature of from 0-25xc2x0 C. and is usually complete in 1-4 h at 0-25xc2x0 C. The product can be readily isolated by simple aqueous work-up.

The 1,3-dipolar cycloaddition reaction of the present invention involves reaction between an in situ generated nitrileimine (V, 1,3-dipole) and a dipolarophile, such as a substituted alkene derivative (VI or VIa). This cycloaddition reaction regiospecifically generates the corresponding substituted pyrazoline (VII or VIIa). The preferred solvent for the cycloaddition reaction is EtOAc.
Generation of nitrileimine 1,3-dipole (V) can be achieved by reacting a base with its precursor (IVa-c). The preferred base is a trialkylamine, such as triethylamine or Hunig""s base, or a cyclic tertiary amine, such as NMM. Preferably, about 2-3 equivalents of base are used.
Factors like the reactivities of 1,3-dipole precursors (IVa-e) and dipolarophiles (VI or VIa) can affect the cycloaddition reaction rate. Therefore, the reaction temperature and time may be varied. Qualitatively, the order of the reactivity of the 1,3-dipole precursors (IV) is: hydrazonoyl mesylate (IVc) greater than hydrazonoyl bromide (IVa), tosylate (IVd), benzenesulfonate (IVe) greater than  greater than hydrazonoyl chloride (IVb). The order of the reactivity of the dipolarophile (VI) is: alkyl acrylate (VIa) greater than N-aryl acrylamide greater than N-biaryl acrylamide. When an alkyl acrylate (VIa is reacted with hydrazonoyl bromide (IVa) or hydrazonoyl sulfonates (IVc-e)), the cycloaddition reaction can be done at room temperature in about 4-12 h. However, the cycloaddition reaction between hydrazonoyl chloride (IVb) and dipolarophiles (VI or VIa) is preferably run at elevated temperature (50-80xc2x0 C.) for 12-24 h.
With a monosubstituted alkene as dipolarophile (VI), such as ethyl acrylate (VIa) or N-aryl/biaryl acrylamide, the 1,3-dipolar cycloaddition reaction regiospecifically generates 5-substituted pyrazoline (VII or VIIa) as the only product.
Even though there are many oxidative dehydrogenation methodologies reported in the literature for the preparation of substituted pyrazoles (VIII) from the corresponding pyrazolines (VII), none of them can be practically employed on a large-scale synthesis. Thus, the present invention involves two novel methods for the oxidation of the cycloaddition product pyrazoline (VII or VIIa) to pyrazole (VIII or VIIIa).

This process involves a reaction between a substituted pyrazoline (VII or VIIa) and N-chlorosuccinimide (NCS). The electrophilic chlorinated pyrazoline intermediate undergoes an in situ dehydrohalogenation to produce the corresponding pyrazole (VIII or VIIIa). Preferably, about 1.0-1.1 equivalents of N-chlorosucinimide (NCS) are used in the reaction. Excess NCS results in the undesired chlorination of the aromatic ring. Thus, it is preferable to minimize the amount of NCS used.
The preferred solvent for this aromatization reaction is THF. A polar solvent such as DMF was found to result in the formation of the aromatic ring chlorination by-product. The reaction is preferable run at 0-25xc2x0 C. At room temperature, the reaction is usually complete in about 1-2 h.
Aromatic ring chlorination by-product is observed when the substrate pyrazoline (VII or VIIa) contains an electron-donating functional group(s) on its aromatic ring. Therefore, this method should be used only when the substrate pyrazoline (VII or VIIa) is substituted with electron-withdrawing functional group(s).
The oxidation product, pyrazole (VIII or VIIIa), can be isolated from the reaction mixture through routine aqueous work-up. The succinimide generated from the reaction dissolves in water. Therefore, it can be extracted readily into the aqueous layer of the work-up mixture.

This process involves a reaction between a substituted pyrazoline (VII or VIIa) and oxygen in air under basic conditions. The enolate of 5-carboyxlate/carbamoyl substituted pyrazoline (VII or VIIa) is oxidized by oxygen in air to produce the corresponding pyrazole (VIII or VIIIa). Preferably, oxygen in air, 7% oxygen in nitrogen, or pure oxygen as is used as the oxidant. The preferred oxygen source of large scale reaction is oxygen in air (22%) or oxygen in nitrogen (7%). A relatively strong base is used to generate the corresponding substituted pyrazoline (VII or VIIa) enolate. The preferred base is potassium tert-butoxide. A polar, aprotic solvent is preferred. The most preferred solvent is DMF or DMAC (N,N-dimethylaminoacetamide). The reaction is run from xe2x88x9225-25xc2x0 C., with the preferred temperature range being xe2x88x9215-5xc2x0 C. The reaction is usually complete in 1-8 h at xe2x88x9215-5xc2x0 C. The reaction time is also dependent on the oxygen source employed.
This protocol is applicable to the oxidation of all the pyrazolines (VII or VIIa), no matter what their aromatic substitution patterns are. Therefore, it can be used for pyrazolines with electron-donating functional group(s) on their aromatic rings.

The Pd(0) catalyst used in the Suzuki coupling is preferably Pd(PPh3)4. About 1-5% equivalents of the catalyst are used to catalyze this coupling reaction with 2% being preferred. About 1.0-1.5 equivalents of an arylboronic acid are used, with 1-2 equivalents being preferred. A base is used to promote the Suzuki coupling reaction. The preferred base is an inorganic salt, such as potassium carbonate or sodium carbonate. The most preferred base is sodium carbonate. A mixed solvent system is used for this Suzuki coupling reaction. The preferred solvent system is toluene/ethanol/water (2-4:1:1 v/v/v). Preferably the reaction is run at elevated temperature, the preferred temperature range being 70-80xc2x0 C. Usually, the reaction is complete in 4-20 h at 70-80xc2x0 C.

A selected class of oxidation reagents can be used to oxidize the thiomethyl (xe2x80x94SMe) functionality to the corresponding sulfone (xe2x80x94SO2Me). The preferred oxidants are mCPBA and Oxone(copyright). About 2-10 equivalents of mCPBA or Oxone(copyright) are used to do this oxidation reaction, with 2-5 eqivalents being preferred. Several different solvents or solvent systems are used for this oxidation reaction. The choice for the solvent or solvent system is dependent on the oxidant used for the reaction. With mCPBA as an oxidant, ethyl acetate (EtOAc) is preferred. With Oxone(copyright) as an oxidant, the preferred solvent system is a mixture of acetone and water in a volume ratio of one to one. The oxidation reaction can be run at 25-50xc2x0 C., depending on the oxidant used for the reaction. With mCPBA as an oxidant, the oxidation reaction can be run at room temperature (20-25xc2x0 C.). But, when Oxone(copyright) is used as an oxidant, the reaction is run at elevated temperature, the preferred temperature range being 40-50xc2x0 C. Generally, the reaction is complete in 5-20 h at 20-50xc2x0 C.

Reduction of the cyano group to a benzylamine can be achieved with a chemical reducing reagent, such as NaBH4, or via Pd(0) catalyzed hydrogenation. The preferred reduction procedure is palladium catalyzed hydrogenation. About 1-2% (weight) of the palladium on charcoal (5% or 10%) can be used. The preferred solvent for the hydrogenation reaction is ethanol. The reaction is normally run at 20-25xc2x0 C. Usually, the reaction is complete in 4-6 h at 20-25xc2x0 C. under 50-55 psig hydrogen pressure. When the reaction is conducted in the existence of an acid, such as hydrochloric acid (HCl), the corresponding salt, such as benzylamine hydrochloride salt, is obtained. When the reduction reaction is conducted in the existence of an electrophile that is used for the in situ protection of the generated benzylamine, such as di-tert-butyl dicarbonate (Boc2O) or trifluoroacetic acid anhydride (TFAA), the corresponding protected benzylamine (Boc or TFA) is obtained.

Converting of the ortho fluoro/cyano substituents to the corresponding aminobenzisoxazole functionality in ring D is achieved in two ways. The first method involves a two-step sequential reaction. Substitution of the fluoro functionality ortho to the cyano group with an acetone oxime in the existence of a base, such as potassium tert-butoxide or NaH, in anhydrous solvent, such as THF or DMF, generates the corresponding acetone oxime substituted intermediate. This intermediate is subsequently converted into the desired aminobenzisoxazole ring by treating with an acid. About 2-4 equivalents of acetone oxime are used for this substituted reaction. The preferred base is sodium hydride. The anhydrous DMF is the preferred solvent. At 0-25xc2x0 C., the substution reaction is complete in 1-2 h.
The second method involves a one-step reaction between fluoro/cyano substituted substrate and an acetohydroxamic acid. Potassium carbonate is preferably used as the base to promote the reaction. Normally, 5-10 equivalents potassium carbonate is used for the reaction. The preferred solvent system is a mixture of DMF and water in a volume ratio 10-15 to 1. The reaction is conducted at 20-30xc2x0 C. At such a temperature range, the reaction is usually complete in 10-15 h.

The Boc protection group is removed to release the corresponding benzylamine by treating the N-Boc benzylamine with an acid. The typical acid used for this deprotection reaction is hydrochloric acid (HCl). The preferred HCl form is 5 to 6 N HCl solution in isopropyl alcohol (IPA). By treatment the corresponding Boc protected benzylamine with excess amount of HCl solution in isopropyl alcohol (IPA) at 20-25xc2x0 C. for several hours, the corresponding benzylamine hydrochloride salt is generated. Normally, 1-5 equivalents of HCl solution in isopropyl alcohol is used.
Trifluoroacetic acid (TFA) is also useful to remove the Boc group. The resulting deprotection product is the corresponding benzylamine trifluoroacetic acid salt. Normally, the excess amount of trifluoroacetic acid is used. The deprotection reaction is also run at 20-25xc2x0 C. The reaction is usually complete in 2-10 h.

Trifluoroacetyl protection group of benzylamine is removed by treating the corresponding TFA protected benzylamine with an inorganic base, such as sodium hydroxide or potassium hydroxide, or an inorganic salt, such as potassium carbonate. The preferred base is potassium carbonate. Normally, 1 to 4 equivalents of potassium carbonate are used for the reaction. Alkyl alcohol, such as methanol or ethanol, is used as solvent. The reaction is run at 20-60xc2x0 C. The preferred temperature range is 50-60xc2x0 C. Normally, the reaction is complete in 2 to 10 h at 50-60xc2x0 C. The deprotection reaction under such a condition generates the corresponding benzylamine as a free base.

Removal of the tert-butyl group to release the corresponding sulfamide is also conducted in an acidic condition. The preferred acid used for this reaction is a 5 to 6 N hydrochloric acid solution in isopropyl alcohol. Normally, an excess of hydrogen chloride is employed. The isopropyl alcohol, which makes hydrogen chloride solution, is also a reaction solvent. The reaction is usually run at an elevated temperature. The preferred temperature range is 70-80xc2x0 C. The reaction is usually complete in 30 to 50 hours at 70-80xc2x0 C.